ABSTRACT Despite advances in therapies for breast cancer, this disease remains a significant cause of mortality in women. Triple negative breast cancer (TNBC) patients have the worst prognosis and survival outcome relative to other breast cancer subtypes. Therefore, much interest surrounds the development of systemic novel targeted therapeutics; however, little is known about how these drugs affect the surrounding non-tumor cells within the tumor microenvironment. Understanding how systemically-delivered breast cancer-targeted therapies interact with non-tumor cells such as infiltrating macrophages is necessary for elucidating how cells become drug resistant and for developing more effective and durable therapies in cancer patients. The Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is activated in TNBC and is an attractive therapeutic target. New therapies in clinical trials aim to inhibit JAK/STAT signaling components, such as STAT5, to turn off this ?switch? in tumors that signal for growth and proliferation1. We find this component of the JAK/STAT signaling pathway is also robustly activated in macrophages in response to TNBC tumor cell-derived factors. We hypothesize that although inhibition of the JAK/STAT pathway may act on the primary tumor directly, the inhibitor alters a delicate balance in the microenvironment that influences infiltrating macrophages from an anti-tumor immune response to a pro-inflammatory and thus, pro-tumorigenic response. Our goal is to define the functional contributions of STAT5 to macrophage polarization within the tumor microenvironment and to macrophage-mediated resistance of mammary tumors to JAK/STAT inhibition. To address these questions, this proposal will employ use of mouse mammary tumor models and clinically- relevant JAK/STAT inhibition strategies to delineate the signaling components responsible for creating this shift from tumor-hostile to tumor-friendly, as well as, provide rationale for potential therapeutic interventions to maintain an anti-tumor response against TNBC.